Parkinson's disease (PD) is a progressive disorder of the central nervous system affecting over 1 million people in the United States. Clinically, the disease is characterized by a decrease in spontaneous movements, gait difficulty, postural instability, rigidity and tremor. Both men and women are affected. The frequency of the disease is considerably higher in individuals over age 50, even though there is an alarming increase of patients of younger age. Due to the increased life expectancy in this country and worldwide, an increasing number of people will be victims of Parkinson's disease.
The major symptoms of the disease were originally described in 1817 by an English physician, Dr. James Parkinson, who called it “Shaking Palsy”. It was not until the 1960's, however, that pathological and biochemical changes in the brain of patients were identified, leading to treatments of the disease opening the way to the first effective medication for the disease.
Parkinson's disease is caused by the degeneration of the pigmented neurons in the Substantia Nigra of the brain, resulting in decreased dopamine availability. Treatment has been directed to increasing the amount of dopamine availability, or to removing the degenerated neurons, and include both medication and surgical treatment.
Medication, including the administration of the drug levodopa, has been the standard treatment for Parkinson's disease. Levodopa is a dopamine precursor, a substance that is transformed into dopamine by the brain. Once it reaches the brain, levodopa is converted to dopamine which replaces the same substance not present in sufficient amounts in Parkinson's patients. The prescription of high dosages of levodopa was the first dramatic breakthrough in the treatment of PD. Treatment with levodopa does not, however, prevent the progressive changes of the brain typical of Parkinson's disease. The drug may also produce side effects in some people, due to its change to dopamine before reaching the brain. Thus, patients experienced debilitating side effects, including severe nausea and vomiting.
The simultaneous administration with levodopa of substances inhibiting this change allows a higher concentration of levodopa to reach the brain and also considerably decreases the side effects. For example, levodopa/carbidopa (Sinemet) represented a significant improvement. The addition of carbidopa prevents levodopa from being metabolized in the gut, liver and other tissues, and allows more of it to get to the brain. Therefore, a smaller dose of levodopa is needed to treat symptoms, and the unpleasant side effects are greatly reduced, though not absent.
Some new drugs have recently been approved offering a wider choice of medications for the patient. For example, Symmetrel (amantadine hydrochloride), originally an anti-flu medication, is though to work in PD by either blocking the reuptake of dopamine or by increasing the release of dopamine by neurons, thereby increasing the supply of dopamine in the synapses. It is thus called an indirect-acting dopamine agonist, and is widely used as an early monotherapy, with the more powerful Sinemet added when needed. When its benefits seem to lessen, stopping the drug for a short period and then reintroducing it seems to again provide efficacy, according to some clinicians.
Selegiline or deprenyl (Eldepryl) has been shown to delay the need for Sinemet when prescribed in the earliest stage of PD, and has also been approved for use in later stages to boost the effects of Sinemet. Dopamine agonists are drugs that activate the dopamine receptor directly, and can be taken alone or in combination with Sinemet. Agonists available in the United States include bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapex) and andropinirole (Requip).
COMT inhibitors such as tolcapone (Tasmar) and entacapone (Comtan), represent a new class of Parkinson's medications. These drugs must be taken with levodopa. They prolong the duration of symptom relief by blocking the action of an enzyme which breaks down levodopa before it reaches the brain.
Other drugs include anticholinergics (trihexyphenidyl, benztropine mesylate, procyclidine, etc.), which do not act directly on the dopaminergic system. Instead they act to decrease the activity of the balancing neurotransmitter, acetylcholine. Since it is known that PD relates primarily to decreased activity of dopamine, one avenue of treatment has been to decrease the cholinergic system to equal that of the dopaminergic system. Most effective in the control of tremor, these drugs may be contraindicated in certain older patients since they tend to cause confusion and hallucination.
Unfortunately, all of the medications currently available exhibit undesirable side effects. Like the symptoms of PD itself, the side effects caused by Parkinson's medications vary from patient to patient. They may include dry mouth, nausea, dizziness, confusion, hallucinations, drowsiness, insomnia, and other unwelcome symptoms. Some patients experience no side effects from a drug, while others have to discontinue its use because of them.
Thus, other treatments involve surgical intervention. One widely utilized surgical procedure is a pallidotomy. This procedure has a long history in the treatment of Parkinson's disease, but it fell out of favor with the advent of levodopa. In recent years it has gained new popularity, mainly because magnetic imaging now allows it to be performed with far greater precision. Pallidotomy is indicated for patients who have developed dyskinetic movements in reaction to their medications. It targets the source of these unwanted movements, the globus pallidus, and uses an electrode to destroy the trouble-causing cells. As with any surgical procedure, there are risks involved. The most serious is the possibility of stroke; other risks include partial loss of vision, speech and swallowing difficulties, and confusion, as well as the general risks associated with surgery.
A related procedure is deep brain stimulation. Like pallidotomy, this technique also seeks to stop uncontrollable movements. It is based on the technology of cardiac pacemakers. Electrodes are implanted in the thalamus or globus pallidus and connected to a pacemaker-like device, which the patient can switch on or off as symptoms dictate.
All of the treatments described above suffer from drawbacks, some serious, which debilitate the patient and compromise the quality of life. Moreover, none of these treatments provide a cure for the disease. Thus, what is needed are treatments that alleviate the symptoms of PD without disrupting normal neuronal functioning. Preferably, such treatments would also affect a cure of PD.